Second generation anti-androgens and androgen deprivation therapy with radiation therapy in the definitive management of high-risk prostate cancer.

BACKGROUND: Evolving data suggest that men with high-risk localized prostate cancer may benefit from more potent androgen receptor inhibition in the context of curative intent radiotherapy. Recently updated American Society for Clinical Oncology (ASCO) evidence-based guidelines and the National Comprehensive Cancer Network (NCCN) Guidelines have updated recommendations for the consideration of adding second generation anti-androgens to androgen deprivation therapy (ADT) in men receiving radiation therapy (RT) for noncastrate locally advanced high and very high risk nonmetastatic or node positive prostate cancer. METHODS AND RESULTS: We conducted a comprehensive review of existing published and abstract presented evidence behind RT with ADT for the definitive management of high-risk prostate cancer, particularly focused on the current phase II and III trial evidence for the addition of second generation anti-androgens to ADT in definitive RT treatment of high-risk prostate cancer and specifically focused on the recent STAMPEDE trial results with abiraterone acetate. We review the biological mechanisms in which second generation anti-androgens may help mitigate ADT resistance and provide radiosensitization through inhibition of DNA repair. Finally, we discuss ongoing clinical trials of potent androgen receptor (AR) inhibitors with ADT in this non-metastatic high-risk radiotherapy setting that may inform on future treatment guidelines. CONCLUSIONS: Recent data suggest an overall survival benefit as well as increased probabilities of disease free and metastasis free survival in men with high and very high-risk localized, node positive, and oligometastatic hormone sensitive prostate cancer with abiraterone acetate and prednisone and support the use of potent AR inhibitors in this setting after informed decision making.

Prognostic nutritional index is an independent prognostic factor for treatment response, survival and drug choice in metastatic castration-resistant prostate cancer treated with abiraterone acetate or enzalutamide.

PURPOSE: We designed this study to identify the prognostic value of baseline prognostic nutritional index (PNI) in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate or enzalutamide. METHODS: 101 mCRPC patients were included. PNI was calculated using formula 10 x serum albumin value (gr/dL) + 0.005 × total lymphocyte count (per mm3). ROC analysis was used for determining prognostic PNI value. RESULTS: The statistically significant cut-off value for PNI was 46.62. Initial PSA response and PSA kinetics (early PSA response and 30 %-50%-90% PSA response at any time) were much better in PNI > 46.62 group than the PNI ≤ 46.62 group (p < 0.01). In multivariate analysis, baseline PNI level >46.62 was an independent predictor of PSA-PFS (HR: 0.42, p < 0.01), radiologic PFS (HR: 0.53, p < 0.01), and OS (HR: 0.42, p < 0.01). In the PNI ≤ 46.62 group, median OS was 7.4 months (95% CI: 4.1-10.7) for the abiraterone acetate subgroup vs. 17.6 months (95% CI: 10.1-25.1) for enzalutamide subgroups (p < 0.01). CONCLUSION: PNI is a useful, independent prognostic marker for mCRPC patients treated with either abiraterone acetate or enzalutamide. Using pre-treatment PNI may help clinicians in the prediction of survival and decision making based on abiraterone acetate or enzalutamide.

What Do the Guidelines Say for Metastatic Prostate Cancer Starting Androgen Deprivation Therapy? National Comprehensive Cancer Network, European Society for Medical Oncology, and European Association of Urology recommendations.

Clinical trial data forms the foundation of how we treat men with metastatic prostate cancer who are initiating therapy. However, clinical trial data does not answer everything; hence, good clinical practice, pragmatism, and occasionally extrapolation drives how we manage these patients. Fortunately, multiple international guideline committees meet regularly and offer clinical guidance. In this mini-review, we focus on the United States National Comprehensive Cancer Network, European Society for Medical Oncology, and European Association of Urology (EAU) recommendations for the initial treatment of metastatic prostate cancer.

Supresión androgénica máxima con acetato de abiraterona en cáncer de próstata hormonosensible / Maximal androgen deprivation with abiraterone acetate in hormone sensitive prostate cancer

OBJETIVO: El tratamiento del cáncer de próstata (CP) metastático ha permanecido inalterado durante más de 70 años fundamentado en la deprivación androgénica (DA). En 2015, a raíz de los estudios CHAARTED y STAMPEDE se estableció que la adición de 6 ciclos de docetaxel a la DA se asociaba significativamente con incremento de la supervivencia. En junio de 2017 los estudios LATITUDE y el brazo G del STAMPEDE demuestran que la adición de Abiraterona junto con Prednisona (5 mg/día) a DA se asocia también a un incremento significativo de supervivencia en los pacientes metastáticos. El presente trabajo analiza estos dos estudios. RESULTADOS: LATITUDE demostró una reducción relativa del riesgo de muerte del 38% (HR=0,62, 95% IC, 0,61-0,76) patente en la práctica totalidad de subgrupos. La reducción del riesgo relativo de progresión radiológica fue del 53 % (HR=0,47,IC 95% 0,39-0,55). Los objetivos secundarios como progresión de PSA, tiempo a quimioterapia o a nuevo evento esquelético también son significativamente retrasados. STAMPEDE también demuestra que la combinación con Abiraterona+prednisolona se asocia a un incremento relativo de SV del 37% (HR=0,63;95% IC, 0,52-0,76; p < 0,001) en pacientes M1, no así en los M0. La supervivencia libre de progresión fue muy mejorada en este brazo (HR=0,29;95% IC 0,25-0,34, p < 0,001). Los efectos secundarios referidos muestran el patrón conocido de exceso mineralcorticoide con incremento de HTA, hipokaliemia y elevación de enzimas hepáticas. CONCLUSIONES: La comparación indirecta de los trabajos de docetaxel y abiraterona confirma que tanto poblaciones, como resultados, son superponibles. Dos meta-análisis indirectos comparativos (>6000 pacientes) otorgan beneficio marginal a abiraterona. A favor de Abiraterona juega el ser una medicación oral, cómoda, con buen perfil de tolerancia y efectos secundarios de fácil manejo, útil en pacientes con frecuencia añosos y frágiles en los que la QT pudiera no estar indicada, aún a costa de una exposición al fármaco es más prolongada y de su actual precio. Futuros ensayos, en curso, determinará el perfil de pacientes idóneo, su posicionamiento en el tiempo o una potencial asociación de ambos

OBJECTIVES: Prostate cancer is linked to bone disease by two different entities. On one hand, androgen deprivation therapy (ADT) usually causes osteoporosis, on the other a great number of patients with advanced prostate cancer will present bone bicametastases, that condition not only their vital prognosis but also an important quality of life deterioration. METHODS: We performed a bibliographic review on both the physiology and therapy of osteoporosis secondary to ADT and bone metastasis in prostatic neoplasias. RESULTS: Osteoporosis: Long term ADT is associated with osteopenia/osteoporosis in 80% of the patients, with a 5-20% incidence of osteoporotic fractures. We should monitor bone mineral density before starting ADT therapy and during treatment. Treatment is based on risk factors reduction, regular physical exercise, calcium and vitamin D supplements, and drugs such as biphosphonates or denosumab. Bone metastasis: Currently, both zolendronic acid and denosumab have approval for the prevention of skeletal events in patients with castration resistant prostate cancer (CPRC). Although the last one seems to be more effective, it is associated with a higher risk of hypocalcemia and jaw osteonecrosis so that the choice of drug must be individualized in every patient. The duration of treatment is not clear. Currently, the indication for the use of this drugs in earlier phases of advanced disease is not approved. CONCLUSIONS: Comprehensive management of the patient with advanced prostate cancer should include the study and treatment of osteoporosis and bone metastases. Currently, very effective therapies are available for both entities

Comparison of Alternative Androgen Receptor-axis-targeted Agent (ARATA) and Docetaxel as Second-line Therapy for Patients With Metastatic Castration-resistant Prostate Cancer With Progression After Initial ARATA in Real-world Clinical Practice in Japan.

BACKGROUND: The objective of the present study was to assess the oncologic outcomes of patients receiving second-line therapy against metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: The present study included 222 consecutive mCRPC patients with progression during initial androgen receptor-axis-targeted agent (ARATA) therapy with either abiraterone acetate (AA) or enzalutamide (Enz). Of these 222 patients, 108 subsequently received an alternative ARATA (AA-to-Enz, n = 49; Enz-to-AA, n = 59) and 114 received docetaxel (DTX; AA-to-DTX, n = 54; Enz-to-DTX, n = 60). RESULTS: The prostate-specific antigen (PSA) level in the 114 patients receiving DTX was significantly greater than that in the 108 patients receiving ARATA. However, no significant differences were found in the remaining parameters between the 2 groups. The PSA response rate, PSA progression-free survival (PFS), and overall survival (OS) during second-line therapy in the DTX group (n = 114) were significantly superior to those for the ARATA group (n = 108; PSA response rate, 42.1% vs. 21.3%; median PSA PFS, 7.2 vs. 4.2 months; median OS, 17.5 vs. 14.5 months). Similar trends were confirmed by comparing these outcomes among 4 therapy groups, with significant differences (PSA response rate, Enz-to-AA vs. AA-to-DTX and Enz-to-AA vs. Enz-to-DTX; PSA PFS, AA-to-Enz vs. Enz-to-AA, AA-to-Enz vs. AA-to-DTX, Enz-to-AA vs. AA-to-DTX, and Enz-to-AA vs. Enz-to-DTX; and OS, Enz-to-AA vs. AA-to-DTX and Enz-to-AA vs. Enz-to-DTX). Furthermore, the introduction of DTX was independently associated with improved PSA PFS, but not OS, on multivariate analysis. CONCLUSION: Favorable oncologic outcomes can be expected with DTX treatment, rather than with alternative ARATA, for mCRPC patients after failure of an initial ARATA.

Comparative Assessment of Efficacies Between 2 Alternative Therapeutic Sequences With Novel Androgen Receptor-Axis-Targeted Agents in Patients With Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: The objective of this study was to compare the efficacies of sequential therapies with novel androgen receptor-axis-targeted (ARAT) agents in patients with docetaxel-naïve metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: This study included 108 consecutive patients with mCRPC who sequentially received abiraterone acetate (AA) and enzalutamide (Enz), in either order, without prior treatment with docetaxel. The combined prostate-specific antigen (PSA) progression-free survival (PFS) was defined as the sum of PFS1 and PFS2, representing PSA PFSs on the first and second ARAT agents, respectively. RESULTS: Of these patients, 49 and 59 received ARAT therapy with the AA-to-Enz sequence (AA-to-Enz group) and with the reverse sequence (Enz-to-AA group), respectively. No significant differences in the baseline characteristics were noted between the 2 groups. In the overall patient population, the PSA response rate to the second-line ARAT agent (21.3%) was significantly lower than that of the first-line ARAT agent (58.3%). The combined PSA PFS in the AA-to-Enz group (median, 18.4 months) was significantly superior to that of the Enz-to-AA group (median, 12.8 months). Furthermore, multivariate analysis identified the treatment sequence (ie, AA-to-Enz vs. Enz-to-AA group) in addition to performance status as an independent predictor of combined PSA PFS in these patients. However, there was no significant difference in overall survival (OS) between the 2 groups. CONCLUSIONS: Although cross-resistance between ARAT agents is a common phenomenon in docetaxel-naïve patients with mCRPC, different efficacies were observed favoring the AA-to-Enz rather than Enz-to-AA sequence in this series with respect to combined PSA PFS but not OS.